Multiple Sclerosis: Relapsing and Progressive Forms
Multiple sclerosis (MS) is a neurological disease affecting more than 1 million people worldwide. It is the most common cause of neurological disability in young and middle-aged adults and has a major physical, psychological, social and financial impact on subjects and their families, friends and bodies responsible for health care.
It is generally assumed that, initially, MS is mediated by some autoimmune process possibly triggered by infection and superimposed upon a genetic predisposition. It is a chronic inflammatory condition that damages the myelin of the central nervous system (CNS). The pathogenesis of MS is characterized by the infiltration of lymphocytes (i.e. autoreactive T-cells) from the circulation directed against myelin antigens into the CNS. In addition to the inflammatory phase in MS, axonal loss occurs early in the course of the disease and can be extensive over time, leading to the subsequent development of progressive, permanent, neurologic impairment and, frequently, severe disability. Symptoms associated with the disease include fatigue, spasticity, ataxia, weakness, bladder and bowel disturbances, sexual dysfunction, pain, tremor, paroxysmal manifestations, visual impairment, psychological problems and cognitive dysfunction.
Various MS disease stages and/or types are described in Multiple Sclerosis Therapeutics (Duntiz, Ed. Rudick and Goodkin, London: Taylor & Francis, 1999). Among them, relapsing-remitting multiple sclerosis (RRMS) is the most common form at the time of initial diagnosis. At the time of diagnosis, between 80% and 90% of MS patients have RRMS. This form of MS is characterized by recurring relapses, i.e. acute episodes, of neurological symptoms followed by recovery periods (remissions). In around 80% of the patients with RRMS, this form later develops to secondary progressive multiple sclerosis (SPMS) around 19 years after disease onset.
When a patient has developed SPMS, disease progression proceeds with or without occasional relapses with no or only minor remissions between relapses and is characterized symptomatically by a continuous worsening of disability, independent of relapses (if present). Symptoms that indicate a shift towards SPMS include a steady increase in weakness and incoordination; stiff, tight leg muscles; bowel and bladder problems; greater fatigue, depression, and problems of thinking. In general, the number of inflammatory infiltrates decreases, while neurodegeneration becomes a more prominent feature of SPMS.
However, recently it has been discovered that inflammation in the brain does not only occur in RRMS patients, but also in SPMS patients. Furthermore, in patients with SPMS, inflammation in the meninges can be found. These immune aggregates are T-cell and B-cell rich structures. Cortical tissue next to these structures shows a significantly increased pathology (Serafini et al, 2004). It has been found that the extent of inflammation in the meninges correlates with the amount of neurodegeneration; furthermore these structures have been reported in SPMS patients only—they have not been observed in RRMS or PPMS patients (Magliozzi et al 2007). SPMS patients with post-mortem identified CNS aggregates had an early disease onset, faster conversion to progressive MS and rapid morbitity (Howell et al 2011). Thus, inflammation seems to drive tissue degeneration at least in some patients.
Although RRMS can be unpredictable, the pattern of clear attacks followed by recovery typically is consistent. With SPMS, relapses tend to be less distinct and, depending on many factors, they may happen less often or not at all. However, when relapses do occur in SPMS patients, their recovery normally is not as complete as in RRMS patients.
Although several drugs are known for treating RRMS, SPMS is in general more difficult to treat.
Marketed Monotherapies for MS
There are currently a number of disease-modifying medications approved for use in relapsing MS (RMS). These include the non-oral medications interferon beta 1-a (e.g. Avonex®, Rebif®, Plegridy®), interferon beta 1-b (Betaseron®, Extavia®), glatiramer acetate (Copaxone®), mitoxantrone (Novantrone®), natalizumab (Tysabri®) and alemtuzumab (Lemtrada®); and the oral medications fingolimod (Gilenya®), teriflunomide (Aubagio®) and dimethyl fumarate (Tecfidera®). Most of these medications are believed to act as immunomodulators. Mitoxantrone and natalizumab are believed to act as immunesuppressants. However, the mechanisms of action of each have been only partly elucidated.
Other therapeutic approaches include symptomatic treatment (which refers to all therapies applied to improve the symptoms caused by the disease) and treatment of acute relapses with corticosteroids. While steroids do not affect the course of MS over time, they can reduce the duration and severity of attacks in some subjects.
Examples of Monotherapies for MS being Under Development
Siponimod
Siponimod belongs to the class of drugs called sphingosine 1-phosphate (S1P) receptor modulators. Another member of said group is fingolimod (Gilenya®) which is marketed to treat RRMS.
Siponimod has been tested in a phase II trial where it showed dose-dependent efficacy in treating RRMS (i.e. the BOLD trial) when given oral at a doses of 0.25 mg, 0.5 mg, 1.25 mg, 2 mg and 10 mg.
S1P receptor modulators are known to block the capacity of leukocytes to migrate from lymph nodes into the peripheral blood. It can sequester lymphocytes in lymph nodes, preventing them from moving to the central nervous system for auto-immune responses in multiple sclerosis.
However, siponimod crosses the blood-brain-barrier and may also have a direct beneficial effect on cells in the CNS. S1P receptor modulators have been reported to stimulate the repair process of glial cells and precursor cells after injury (Alejandro Horga et al, Expert Rev Neurother 8(5), 699-714, 2008) which could form the basis of efficacy in SPMS.
Laquinimod
Laquinimod has been suggested as an oral formulation for the treatment of RRMS. It has been tested in two phase III trials where it showed efficacy in treating RRMS (i.e. the BRAVO trial and the ALLEGRO trial) when given oral at a dose of 0.6 mg once daily over a period of 24 months.
Laquinimod and its sodium salt form are described, e.g. in U.S. Pat. No. 6,077,851. The mechanism of action of laquinimod is not fully understood.
Combination Therapy of Disease-Modifying Medications
The administration of two drugs to treat a given condition, such as MS, raises a number of potential problems. In vivo interactions between two drugs are complex. The effects of any single drug are related to its absorption, distribution, and elimination. When two drugs are introduced into the body, each drug can affect the absorption, distribution, and elimination of the other and hence, alter the effects of the other. For instance, one drug may inhibit, activate or induce the production of enzymes involved in a metabolic route of elimination of the other drug.
In WO2013055907, a combination comprising the experimental drug laquinimod and the marketed drug fingolimod is tested in an animal model for RRMS (i.e. MOG-induced experimental autoimmune encephalomyelitis (EAE) in the C57Bl/6 strain of mice). This model is an established model to test the efficacy of medicines as preventive agents to treat RRMS. A combination of 10 mg/kg of laquinimod with 0.3 mg/kg of fingolimod showed a synergistic effect in preventing disease severity.
However, in other examples of drug combinations, lack of synergy or even antagonism was seen and other unwanted side effects were reported.
The combined administration of fingolimod and interferon has been shown to abrogate the clinical effectiveness of either therapy (Brod et al, Annals of Neurology, 47, 127-131, 2000). In another experiment, it was reported that the addition of prednisone in combination therapy with interferon beta antagonized its up-regulator effect (Salama et al, Multiple Sclerosis, 9, 28-31, 2003).
In one example, the combination of natalizumab and interferon beta 1-a was observed to increase the risk of unanticipated side effects (Rudick et al, New England Journal of Medicine, 354, 911-923, 2006; Kleinschmidt-DeMasters, New England Journal of Medicine, 353, 369-379, 2005; Langer-Gould, New England Journal of Medicine, 353, 369-379, 2005).
Thus, when two drugs are administered to treat the same condition, it is unpredictable whether each will complement, have no effect on, or interfere with, the therapeutic activity of the other in a subject. Not only may the interaction between two drugs affect the intended therapeutic activity of each drug, but the interaction may increase the levels of toxic metabolites. The interaction may also heighten or lessen the side effects of each drug. Hence, upon administration of two drugs to treat a disease, it is unpredictable what change will occur in the negative side profile of each drug. Additionally, it is difficult to accurately predict when the effects of the interaction between the two drugs will become manifest. For example, metabolic interactions between drugs may become apparent upon the initial administration of the second drug, after the two have reached a steady-state concentration or upon discontinuation of one of the drugs.
Therefore, the state of the art at the time of filing is that the effects of combination therapy of two specific drugs, in particular siponimod and laquinimod, cannot be predicted until the results of a combination study are available.
There is a need to provide effective medicaments for the treatment of autoimmune diseases, e.g. SPMS.